Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 22; pp. 6739 - 6743
• Main Authors: Belanger, David B., Williams, Michael J., Curran, Patrick J., Mandal, Amit K., Meng, Zhaoyang, Rainka, Matthew P., Yu, Tao, Shih, Neng-Yang, Siddiqui, M. Arshad, Liu, Ming, Tevar, Seema, Lee, Suining, Liang, Lianzhu, Gray, Kimberly, Yaremko, Bohdan, Jones, Jennifer, Smith, Elizabeth B., Prelusky, Dan B., Basso, Andrea D.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15-11-2010; Elsevier
• Subjects: Administration, Oral; Animals; Antineoplastic agents; Antitumor agents; Aurora kinase; Aurora kinase inhibitors; Aurora Kinases; Bioavailability; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Female; General aspects; Humans; Imidazo[1,2-a]pyrazine; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Medical sciences; Oral bioavailability; Pharmacology. Drug treatments; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pyrazines - chemistry; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Solvents; Tumor xenograft mouse model; Tumors; Xenograft Model Antitumor Assays; Xenografts; Imidazo[1,2-a]pyrazine; Oral bioavailability; Tumor xenograft mouse model; Aurora kinase inhibitors; Antineoplastic agent; Rat; Angular nitrogen heterocycle; Nitrogen heterocycle; Non-specific serine/threonine protein kinase; Morpholine derivatives; Ovary; Signal transduction; Structure activity relation; Bicyclic compound; Pyrazole derivatives; Chemical synthesis; Dog; Tumor cell; Human; Fissipedia; Carnivora; Enzyme; Transferases; Rodentia; Oral administration; Enzyme inhibitor; Bioavailability; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Treatment; Cell line; Mouse; Animal; Pharmacokinetics; Cancer
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.08.140

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.
We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.